cytarabine injection - 2 G/20 ML SINGLE-DOSE VIAL Warnings and Precautions

WARNINGS

(See boxed WARNING)

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses, and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine injection.

Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine injection) has been reported following some experimental dose schedules for cytarabine injection. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction, including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard treatment programs using cytarabine injection. If experimental high dose therapy is used, do not use a preparation containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine injection at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients.

Use in Pregnancy

Cytarabine Injection can cause fetal harm when administered to a pregnant woman. Cytarabine causes abnormal cerebellar development in the neonatal hamster and is teratogenic to the rat fetus. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant.

A review of the literature has shown 32 reported cases where cytarabine injection was given during pregnancy, either alone or in combination with other cytotoxic agents:

Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis.

Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure.

There were seven infants with various problems in the neonatal period, including pancytopenia, transient depression of WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased lgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis.

Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on cytarabine should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

PRECAUTIONS

1.
General Precautions
Patients receiving Cytarabine Injection must be monitored closely. Frequent platelet and leucocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control.
When large intravenous doses are given too quickly, patients are frequently nauseated and may vomit for several hours post-injection. This problem tends to be less severe when the drug is infused.
The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine injection treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor.
Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine injection.
Like other cytotoxic drugs, Cytarabine Injection may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.
Acute pancreatitis has been reported to occur in a patient receiving Cytarabine Injection by continuous infusion and in patients being treated with Cytarabine Injection who have had prior treatment with L-asparaginase.
2.
Information for patient
Not applicable.
3.
Laboratory tests
See General Precautions.
4.
Drug Interactions 
Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine injection or procarbazine.

Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.
An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.
Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine injection. This may be due to potential competitive inhibition of its uptake.
5.
Carcinogenesis, mutagenesis, impairment of fertility
Extensive chromosomal damage, including chromatoid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.
6.
Pregnancy
See WARNINGS.
7.
Labor and delivery
Not applicable.
8.
Nursing mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
9.
Pediatric use
See INDICATIONS AND USAGE.

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Warnings and Precautions

WARNINGS

(See boxed WARNING)

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses, and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine injection.

Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine injection) has been reported following some experimental dose schedules for cytarabine injection. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction, including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard treatment programs using cytarabine injection. If experimental high dose therapy is used, do not use a preparation containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine injection at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients.

Use in Pregnancy

Cytarabine Injection can cause fetal harm when administered to a pregnant woman. Cytarabine causes abnormal cerebellar development in the neonatal hamster and is teratogenic to the rat fetus. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant.

A review of the literature has shown 32 reported cases where cytarabine injection was given during pregnancy, either alone or in combination with other cytotoxic agents:

Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis.

Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure.

There were seven infants with various problems in the neonatal period, including pancytopenia, transient depression of WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased lgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis.

Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on cytarabine should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

PRECAUTIONS

1.
General Precautions
Patients receiving Cytarabine Injection must be monitored closely. Frequent platelet and leucocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control.
When large intravenous doses are given too quickly, patients are frequently nauseated and may vomit for several hours post-injection. This problem tends to be less severe when the drug is infused.
The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine injection treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor.
Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine injection.
Like other cytotoxic drugs, Cytarabine Injection may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.
Acute pancreatitis has been reported to occur in a patient receiving Cytarabine Injection by continuous infusion and in patients being treated with Cytarabine Injection who have had prior treatment with L-asparaginase.
2.
Information for patient
Not applicable.
3.
Laboratory tests
See General Precautions.
4.
Drug Interactions 
Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine injection or procarbazine.

Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.
An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.
Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine injection. This may be due to potential competitive inhibition of its uptake.
5.
Carcinogenesis, mutagenesis, impairment of fertility
Extensive chromosomal damage, including chromatoid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.
6.
Pregnancy
See WARNINGS.
7.
Labor and delivery
Not applicable.
8.
Nursing mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
9.
Pediatric use
See INDICATIONS AND USAGE.

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